Huang Y, Wongamorntham S, Kasting J, McQuillan D, Owens R T, Yu L, Noble N A, Border W
Fibrosis Research Laboratory, Division of Nephrology, Department of Medicine, University of Utah, Salt Lake City, Utah 84108, USA.
Kidney Int. 2006 Jan;69(1):105-13. doi: 10.1038/sj.ki.5000011.
Recent evidence suggesting a strong interplay between components of the renin-angiotensin system and key mediators of fibrosis led us to hypothesize that renin, independent of its enzymatic action to enhance angiotensin (Ang) II synthesis, directly increases production of the fibrogenic cytokine transforming growth factor (TGF)-beta. Human or rat mesangial cells (MCs) were treated with human recombinant renin (HrRenin) or rat recombinant renin (RrRenin) and the effects on TGF-beta1, plasminogen activator inhibitor-type 1 (PAI-1), fibronectin (FN) and collagen 1 mRNA and protein were investigated. Blockade of the rat MC renin receptor was achieved using siRNA. HrRenin or RrRenin, at doses shown to be physiologically relevant, induced marked dose- and time-dependent increases in TGF-beta1. These effects were not altered by adding an inhibitor of renin's enzymatic action (RO 42-5892), the Ang II receptor antagonist losartan or the Ang-converting enzyme inhibitor enalapril. RrRenin also induced PAI-1, FN and collagen 1 mRNA and PAI-1 and FN protein in a dose-dependent manner. Neutralizing antibodies to TGF-beta partially blocked these effects. Supernatant and cell lysate Ang I and Ang II levels were extremely low. MC angiotensinogen mRNA was undetectable both with and without added renin. Targeting of the rat renin receptor mRNA with siRNA blocked induction of TGF-beta1. We conclude that renin upregulates MC TGF-beta1 through a receptor-mediated mechanism, independent of Ang II generation or action. Renin-induced increases in TGF-beta1 in turn stimulate increases in PAI-1, FN and collagen I. Thus, renin may contribute to renal fibrotic disease, particularly when therapeutic Ang II blockade elevates plasma renin.
最近有证据表明肾素-血管紧张素系统的各组分与纤维化的关键介质之间存在强烈的相互作用，这使我们推测，肾素独立于其增强血管紧张素（Ang）II合成的酶促作用，可直接增加促纤维化细胞因子转化生长因子（TGF）-β的产生。用人重组肾素（HrRenin）或大鼠重组肾素（RrRenin）处理人或大鼠系膜细胞（MCs），并研究其对TGF-β1、纤溶酶原激活物抑制剂1型（PAI-1）、纤连蛋白（FN）和胶原蛋白1的mRNA及蛋白的影响。使用小干扰RNA（siRNA）阻断大鼠MC肾素受体。HrRenin或RrRenin在显示具有生理相关性的剂量下，可诱导TGF-β1出现明显的剂量和时间依赖性增加。添加肾素酶促作用抑制剂（RO 42-5892）、Ang II受体拮抗剂氯沙坦或血管紧张素转换酶抑制剂依那普利并不会改变这些作用。RrRenin还可剂量依赖性地诱导PAI-1、FN和胶原蛋白1的mRNA以及PAI-1和FN蛋白。TGF-β的中和抗体可部分阻断这些作用。上清液和细胞裂解液中的Ang I和Ang II水平极低。无论添加或不添加肾素，MC血管紧张素原mRNA均无法检测到。用siRNA靶向大鼠肾素受体mRNA可阻断TGF-β1的诱导。我们得出结论，肾素通过受体介导的机制上调MC的TGF-β1，独立于Ang II的生成或作用。肾素诱导的TGF-β1增加继而刺激PAI-1、FN和胶原蛋白I增加。因此，肾素可能促成肾纤维化疾病，尤其是当治疗性Ang II阻断导致血浆肾素升高时。
